Our overall objective is to solve the problem of how proteins fold into their native conformations and then (e.g., as enzymes) interact with substrates and other ligands. For this purpose, we are developing and applying experimental and theoretical techniques to provide an understanding of the internal interactions which stabilize native proteins in aqueous solution. Besides using the conventional methods of protein physical chemistry (including circular dichroism and nuclear magnetic resonance), our emphasis here is on the use of laser-Raman spectroscopy, calorimetry, electric dichroism, dipole moments, statistical mechanics, and conformational energy calculations. These techniques are being applied to specific problems, involving the structures of polypeptides and proteins in solution. Bibliographic references: Burgess, Weinstein, Gabel and Scheraga - Immobilized Carboxy-peptidase A as a Probe for Studying the Thermally Induced Unfolding of Bovine Pancreatic Ribonuclease, Biochemistry, 14, 197 (1975); Shipman and Scheraga - Computation of the Intermolecular Vibrational Modes of a Tetrahedral Water Pentamer at the Core of an Ice- like Water Cluster, J. Phys. Chem., 79, 380 (1975).